Evidence for male-mediated developmental toxicity derives from strong animal data that premating paternal exposures can lead to adverse developmental effects . In addition, there is growing epidemiological evidence that exposures of fathers to environmental toxicants are associated with adverse consequences to the fetus. However, the underlying mechanism for the effects of paternal exposure remain unresolved and is likely to include genetic defects transmitted by sperm. In this regard, a promising new method was recently developed to detect human sperm carrying abnormal numbers of chromosomes (aneuploidy) based on fluorescence in situ hybridization (FISH). Aneuploidy, especially of th sex chromosomes, affects live-born children, has a large paternal contribution, and sperm aneuploidy is know to be inducible after exposures to exogenous aneugenous, both in murine and human males. The objectives of this research are to employ the new sperm aneuploidy assay to investigate the relationship between genetic defects in sperm and th probability of fathering a chromosomally defective child and to determine whether common lifestyle factors predispose men towards producing genetically defective sperm. The aims are to: 1) investigate the relationship between aneuploidy in the child and rates of aneuploidy in the sperm of the father as determined by fluorescence in situ hybridization (FISH). To accomplish this purpose we will measure frequencies of aneuploidy in the sperm of fathers of 40 children with Klinefelters syndrome (XXY). We will compare the frequencies of sperm aneuploidy in those who contributed the extra chromosome with those where the mother contributed the extra chromosome; and 2) determine whether paternal age and common lifestyle factors such as smoking and diet alter the frequencies of aneuploid sperm. Two studies ar designed to accomplish this goal: (a) 85 nonsmoking men distributed from ages 20 to 69 years old, and (b) 40 nonsmokers with 40 heavy smokers. The latter study is also designed to examine the modifying effects of deficient Zn and antioxidant intake on sperm aneuploidy. Conventional clinical semen analyses and high-technology sperm assays of chromatin stability (SCSA), CASA motility, and sperm morphometry by image analysis are included as measures of associated sperm toxicity. This research will provide fundamental information on the predictive value of genetic defects in sperm and on the effects of paternal age, diet and smoking on genetic damage to human sperm. These findings will also provide critical data needed for the design and interpretation of studies of paternal effects of exposure to superfund agents.